Pharmacologically active peptide conjugates having a reduced tendency towards enzymatic hydrolysis

Abstract

The invention is directed to a pharmacologically active peptide conjugate having a reduced tendency towards enzymatic cleavage including a pharmacologically active peptide sequence (X) and a stabilising petide sequence (Z) covalently bound to X.

1 . A peptide conjugate comprising X and Z, 
 wherein X is selected from neuropeptide Y, pancreatic polypeptide, and peptide YY, and any truncated analogue thereof; and Z is a stabilising peptide consisting of 4 to 15 amino acid residues covalently bound by its N terminus to the C terminus end of X, wherein Z comprises (1) residues selected from Glu, Lys, and Met, or (2) Z is a sequence selected from: 
 (i) Lys 4-10 ,  
 (ii) (Lys-Xaa) m ,  
 (iii) (Xaa-Lys) m ,  
 (iv) Lys p -Xaa q ,  
 (v) Xaa p -Lys q ,  
 (vi) Xaa 1 -Lys-Xaa 2 -Lys,  
 (vii) Xaa 1 -Lys-Xaa 2 -Lys-Xaa 2 ,  
 (viii) Xaa 1 -Lys-Xaa 2 -Lys-Xaa 2 -Lys,  
 (x) Xaa 1 -Xaa 1 -Lys-Xaa 2 -Lys,  
 (xi) Xaa 1 -Xaa 1 -Lys-Xaa 2 -Lys-Xaa 2 ,  
 (xii) Lys-Xaa 2 -Lys-Xaa 1 ,  
 (xiii) Lys-Xaa 2 -Lys-Xaa 2 -Xaa 1 ,  
 (xiv) Lys-Xaa 2 -Lys-Xaa 2 -Lys-Xaa 1 ,  
 (xv) Xaa 2 -Lys-Xaa 2 -Xaa 1 ,  
 (xvi) Xaa 2 -Lys-Xaa 2 -Lys-Xaa 1 , and  
 (xvii) Xaa 2 -Lys-Xaa 1 -Lys-Xaa 2 -Xaa 1 ,  
   wherein    each of Xaa, Xaa 1 , and Xaa 2  is, independently, selected from the group consisting of Ser, Thr, Tyr, Asn, Gln, Asp, Glu, Arg, His, and Met;    each of p and q is, independently, an integer fromI to 14, with the proviso that p+q is from 4 to 15;    m is an integer in the range from 2 to 7;    and pharmaceutically acceptable salts thereof.    
     
     
         2 . The peptide conjugate of  claim 1 , wherein Z is 4 to 7 amino acid residues selected from Glu, Lys, and Met.  
     
     
         3 . The peptide conjugate of  claim 1 , wherein Z has an overall charge in the range from 0 to +15 at pH 7.  
     
     
         4 . The peptide conjugate of  claim 3 , wherein Z has an overall charge in the range from 0 to +10 at pH 7.  
     
     
         5 . The peptide conjugate of  claim 4 , wherein Z comprises at least three Lys amino acids.  
     
     
         6 . The peptide conjugate of  claim 1 , wherein each amino acid residue of Z is Glu, Lys, or Met.  
     
     
         7 . The peptide conjugate of  claim 1 , wherein Z has the sequence (Lys) n , wherein n is an integer in the range from 4 to 15.  
     
     
         8 . The peptide conjugate of  claim 7 , wherein Z is (Lys) n  in which n is an integer from 4 to 10.  
     
     
         9 . The peptide conjugate of  claim 8 , wherein Z is Lys 4  (SEQ ID NO: 55), Lys 5  (SEQ ID NO: 56) or Lys 6  (SEQ ID NO: 62).  
     
     
         10 . The peptide conjugate of  claim 9 , wherein Z is Lys 6  (SEQ ID NO: 62).  
     
     
         11 . A peptide conjugate of  claim 1 , wherein Z is bound to the N-terminal of X.  
     
     
         12 . A peptide conjugate of  claim 1 , wherein Z is bound to the C-terminal of X.  
     
     
         13 . A peptide conjugate of  claim 1 , wherein X is neuropeptide Y, or a truncated analog thereof, and Z is Lys 4  (SEQ ID NO: 55), Lys 5  (SEQ ID NO: 56) or Lys 6  (SEQ ID NO: 62).  
     
     
         14 . A peptide conjugate of  claim 1 , wherein X is pancreatic polypeptide, or a truncated analog thereof, and Z is Lys 4  (SEQ ID NO: 55), Lys 5  (SEQ ID NO: 56) or Lys 6  (SEQ ID NO: 62).  
     
     
         15 . A peptide conjugate of  claim 1 , wherein X is peptide YY, or a truncated analog thereof, and Z is Lys 4  (SEQ ID NO: 55), Lys 5  (SEQ ID NO: 56) or Lys 6  (SEQ ID NO: 62).  
     
     
         16 . A method of treating an eating disorder in a subject in need thereof, said method comprising administering to said subject a peptide conjugate of any of claims  1 - 15  in an amount effective to treat said eating disorder.